Dr. Emens is an Assistant Professor in the Department of Oncology at Johns Hopkins. She has completed formal training in basic scientific research and clinical oncology. During her fellowship she participated in the preclinical Work that forms the barns for the trials proposed in this application. She also developed a human whole cell GM-CSF-secreting breast cancer vaccine, and designed a clinical trial that tests it in patients with metastatic breast cancer, directly translating the vaccination regimen and immune monitoring assays from the preclinical to the clinical setting. Her career development plan is to obtain the formal and practical training in clinical research to complement her previous training and position her for a successful career as an independent clinically oriented translational investigator. "Her mentors will be Elizabeth Jaffee, MD and Steven Piantadosi, MD PhD, who will provide mentorship in immunotherapy and clinical trial design and analysis respectively. One promising immunotherapeutic strategy for overcoming drug resistance in advanced breast cancer utilizes whole tumor cells secreting GM-CSF to activate the patient's own immune system to recognize and eliminate cancer cells. Because it is unlikely that this approach will induce durable clinical responses in patients with advanced disease, we have utilized the clinically relevant neu transgenic mouse for developing more potent vaccination strategies. We found that sequencing a neu-targeted, GM-CSF-secreting vaccine with 10w doses of Cyclophosphamide (CY) and Doxorubicin (DOX) augmented the vaccine-activated HER-2/neu-specifie immune response, delaying rates of tumor outgrowth compared to vaccine or drugs alone. This was reflected in enhanced HER-2/neu-specific T helper cell, CTL, and antibody responses. The specific research goals are to: (1) identify the doses of CY and DOX that optimize vaccine-activated immunity in a Phase I trial targeting breast cancer patients with metastatic disease, (2) develop in vitro assays of vaccine-activated immunity using HER-2/neu as a target antigen, and (3) develop a Phase 1FItrial testing the optimal vaccination regimen in patients with high risk primary breast cancer. The overall objective of this proposal is to establish the foundation for a clinical program in breast cancer immunotherapy that integrates GM-CSF-secreting vaccines with other treatment modalities for advanced breast cancer in an additive or synergistic fashion.